any genetic disorder, but Collins chose to focus on cystic fibrosis, in part be- cause of a young woman he had treated as an intern, in 1977. "I became inter- ested in the condition, and frustrated when I tried to learn more about its genesis, and there was nothing there," he said. In 1984, Collins moved to the University of Michigan, and in 1987 he began to collaborate with Lap-Chee T sui and Jack Riordan, researchers in Toronto, to find the exact nature of the cystic-fibrosis mutation. Two years later, the researchers identified the gene and determined its function. Their findings were published as a series of three papers in the journal Science. The discovery of the gene set off a wave of euphoria, with many people convinced that cystic fibrosis would soon be cured. Collins recalled, "You know the affected organs, the lungs and pancreas, you deliver the normal gene, and, bingo! You'd be done." The N .I.H. spent millions of dollars setting up gene- therapy centers to attempt just that. In 1990, a year after the gene was discov- ered, researchers published papers on successful laboratory tests in prestigious journals like Nature and Cell. The New York Times reported, "Scientists have cured cystic fibrosis cells in the lab ora - tory by inserting a healthy version of the gene that causes the disease, an unex- pectedly swift advance that left research- ers almost giddy with delight. The results throw open the door to using human gene therapy to treat the deadly respiratory disorder, the most common fatal genetic ailment in the United States." Yet, despite the successes in the laboratory, patients had an immune reaction to the procedure, rejecting the delivery system that held the normal gene. For those who had invested their hopes in the therapy, the disappointment was devastating. Last November, I vis- ited the Cystic Fibrosis Clinic at Chil- dren's Hospital Boston with Dr. Ahmet Uluer, a pediatric pneumologist and the director of the adult cystic-fibrosis pro- gram. The mood was sombre: a few days earlier, Dean Barnett, a conservative col- umnist and political activist in Boston, who had cystic fibrosis, had died, at the age of forty-one. In one examination room, Sabrina Kelley, a twelve-year-old patient, and her father, Brian, a Massa- 32 THE NEW YORKER, MAY 4, 2009 chusetts state trooper, were waiting for the doctor. Sabrina had been running a fever for several days; during the previous year, she had spent weeks on intravenous antibiotics for sinus infections and lung infections. "Sabrina was born in 1996, when it was all about gene therapy," Brian Kelley said. He paused and looked at Dr. Uluer. "You doctors were sup- posed to :fix it," he said. Kelley has been following the trials of the new drugs, but, he told me, "I have no expectation." D r. Robert Beall, a biochemist who had worked at the N .I.H., joined the Cystic Fibrosis Foundation in 1980 as executive vice-president for medical affairs, and became the president and C.E.O. in 1994. He was determined to find a new approach to treating the un- derlying genetic defect in cystic fibrosis. "I was on a long plane ride and catching up on reading," he recalled. "There was an article in Nature Medicine on high- throughput screening-using auto- mated systems like robots to test hun- dreds of thousands of compounds in search of a drug." Beall sought funding to apply this new technology to cystic- fibrosis research, and in 1998, he ap- proached Roger T sien, a biologist who was working on ways to track proteins and monitor signals in cells using fluorescence. (Tsien won a Nobel Prize in Chemistry last year for this work.) Tsien had co-founded a biotech com- pany, Aurora Biosciences, in San Diego, which utilized the high-through put- screening technology. Realizing that the research would be intensive, and that its results would have a relatively small market, Beall arranged for the foundation to provide Aurora with an initial grant of two million dol- lars. "Basically, we just wanted to see if they could get going," Beall said. The company formatted a system to screen for the chemical compounds that facili- tated chloride transport, but it would need a larger subsidy in order to continue with the research. In 1999, Beall ap- pro ached the Gates Foundation. Wil- liam Gates, Sr., then the head of the foundation, interviewed Beall about the unprecedented idea of correcting a mu- tated protein with a drug that could be taken orally, would work throughout the body, and would restore functioning of diseased organs. 'We sat around his liv- ing-room table and wrote a proposal," Beall told me. "They called us two weeks later and said they were giving us twenty million dollars to start the Aurora proj- ect." The Cystic Fibrosis Foundation contributed seventeen million dollars, from the sale of patent rights to an aero- solized antibiotic. (The foundation often acts as an investor in cystic-fibrosis re- search done by for-profit companies, and sometimes retains the rights to patents on any drugs produced from such re- search.) 'We knocked the socks off the biotech world," Beall said. A few years ago, Beall recruited Joseph O'Donnell, a successful businessman whose twelve- year-old son had died of the disease, and who had served on the foundation's board, to lead an effort to raise a hundred and seventy-five million dollars to con- tribute to more new drug development; so far, he has garnered a hundred and fifty-one million. With more than sixteen hundred known mutations in the cystic-fibrosis gene, the process of finding drugs to address the disease's pathology seemed formidable. But researchers soon real- ized that these mutations could be grouped into categories. One category of mutations produces a protein that is able to insert itself into the membrane of the cell but contains a "rusty gate" that closes off the passage of chloride. Another group of mutations, the most common, prevents the protein from reaching the membrane. A third cate- gory has a so-called "nonsense muta- tion," which causes the cell to abruprly terminate production of the protein, making only a fragment. With the grant from the Cystic Fi- brosis Foundation, scientists on the Au- rora team began screening more than half a million chemical compounds. Once a chemical was found to restore the movement of chloride, the team worked to modify the compound into potable forms that might serve as drugs. Eventu- ally, Aurora identified several com- pounds that would either wedge open